Potassium is an essential element for maintaining health in animals and humans. Potassium ions participate in a number of essential physiological processes, including the maintenance of intracellular tonicity, the transmission of nerve impulses, the contraction of muscles and the maintenance of normal renal functions. Potassium is the predominating cation of intracellular fluids and erythrocytes.
Potassium depletion or potassium deficiency, also known as hypokolemia, can be induced in an animal or human in a variety of ways. Potassium depletion can occur whenever the rate of potassium loss through renal excretion and/or loss from the gastrointestinal tract exceeds the rate of potassium intake. Such depletion usually results slowly as a consequence of prolonged therapy with oral diuretics, primary or secondary hyperaldosteronism, diabetic ketoacidosis, severe diarrhea or inadequate replacement of potassium in patients on prolonged parenteral nutrition.
Potassium depletion due to these causes is usually accompanied by a deficiency of chloride ions. Both such deficiencies could be alleviated if potassium chloride was administered to the human or animal. Further, the most convenient mode of such administration would be to give the human or animal a potassium chloride tablet to ingest orally.
Unfortunately, potassium chloride tablets have been known to produce stenotic and/or ulcerative lesions of the small bowel and deaths, in addition to upper gastrointestinal bleeding. These lesions are caused by high localized concentrations of potassium ion in the region of a rapidly dissolving tablet which injures the bowel wall and thereby produces obstruction, hemorrhage, or perforation.
U.S. Pat. No. 2,921,883 describes the preparation of a wax-matrix solid dosage form of potassium chloride. Although fewer bowel lesions have been observed with wax-matrix tablets compared to enteric coated tablets there are still drawbacks to the use of wax-matrix tablets. The rate of dissolution of the potassium chloride from the matrix may be uneven resulting in large amounts of potassium and chloride ions being released at one time. Wax matrix tablets may tend to lay in one spot in the intestine. It is known that wax-matrix potassium chloride preparations have produced esophageal ulceration in certain cardiac patients with esophogeal compression due to an enlarged left atrium. Physicians' Desk Reference.RTM.(1987), p. 1629, Medical Economics Company Inc., Oradel, NJ 07649.
One way of overcoming the harmful side effects associated with administration of solid potassium chloride is to administer potassium chloride in an aqueous solution. However, there are distinct disadvantages associated with liquid pharmaceutical products. For example, the finished dosage form, i.e., the product which sits on the pharmacy shelf takes up more space than a tablet. Liquids may not be convenient to take for the ambulatory working patient, and breaking and leakage of the container could present a problem. More importantly, liquids tend to be bad tasting and the patient may not take the liquid potassium according to the prescribed doseage schedule.
Effervescent potassium chloride compositions are taught by U.S. Pat. No. 3,903,255. This '255 patent also describes the problems associated with such compositions. Often times an unappetizing scum is formed in solutions prepared from the effervescent tablets. Also, quite often, the effervescent powder does not completely go into solution leaving partially dissolved potassium chloride residue which is difficult for the human or animal to swallow apart from the rest of the liquid.
It is therefore highly desirable to have a solid-dosage form of potassium chloride which does not contain the inherent problems of the prior art tablet, liquid, and effervescent forms described above, yet is conveniently administered as an oral-dosage form.
One such oral-dosage form is a capsule containing microencapsulated potassium salt. Such dosage form is described in U.S. Pat. No. 4,259,315. The '315 patent discloses pharmaceutical compositions suitable for oral administration to monogastric animals consisting of gelatin capsules containing mixtures of microencapsulated potassium salt and a hydrophyllic surfactant external to the microcapsules.
As taught by the '315 patent, microencapsulation in ethyl cellulose shell walls is old in the art. Further, potassium chloride encapsulated with a film of ethyl cellulose is known. U.S. Pat. No. 3,415,758 describes the preparation of microencapsulated potassium chloride via phase separation or coacervation techniques. These microcapsules may also be prepared according to an an air suspension coating process similar to the Wurster air suspension process described in U.S. Pat. Nos. 3,117,027; 3,196,827; 3,241,250 and 3,253,944.
U.S. Pat. No. 4,389,331 describes the preparation of ethyl cellulose microcapsules containing a pharmaceutically active compound by phase separation coacervation where phospholipids are used as a phase-separation inducing agent. U.S. Pat. Nos. 4,411,933 and 4,486,471 describes a similar processes.
There are however, disadvantages associated with the administration of gelatin capsules containing microcapsules having ethyl cellulose shell walls. The microencapsulated potassium chloride can agglomerate during the dissolution of the gelatin capsule. This greatly increases the possibility that the clump of microencapsulated potassium chloride will remain in one spot of the gastrointestinal tract and thus, release high concentrations of potassium and chloride ions which can cause ulceration or lesions.
Surprisingly, it has been found that microcapsules of the invention having shell walls formed of a combination of ethyl cellulose and long chain fatty acid do not tend to agglomerate in the gastrointesinal tract yet still release potassium chloride at the same rate as microcapsules having shell walls formed only of ethyl cellulose. The microcapsules of the invention disperse rapidly in both gastric and intestinal fluids and the shell walls of the invention are stronger than shell walls of ethyl cellulose alone. The microcapsules of the invention are more uniformly spherical than prior art microencapsulated potassium chloride.